Plasma concentrations of zidovudine (ZDV) and other nucleoside analog drugs have shown little correlation with clinical events. Because they must be metabolized intracellularly to elicit a biological effect, intracellular concentrations of the phosphorylated metabolites of nucleoside analogs might correlate with drug effects. The studies herein propose to use a sensitive and reproducible radioimmunoassay method, suitable for routine monitoring of total phosphorylated ZDV in peripheral blood mononuclear cells (PBMC), to define the pharmacokinetics of ZDV phosphorylation in PBMC from patients receiving ZDV, and examine the relation between intracellular concentrations and certain prognostic indicators of HIV disease. This includes a two armed study with a total of 40 patients. One arm will examine the rate of ZDV phosphorylation in ZDV-naive patients and the length of time required to reach steady-state concentrations while on standard dose ZDV (500 mg/day). The second arm will investigate the dose-response in patients on an escalating dose regimen. A two-year study combined both patient groups, and investigates the effects of long-term ZDV therapy on intracellular pharmacokinetics, including clearance and phosphorylation upon re-introduction of drug. Concurrent measurements of the prognostic indicators will be made. This study may suggest that longer dosing intervals and/or lower doses of ZDV are adequate to maintain intracellular concentrations. Additionally, an HPLC/RIA method will be validated and used to determine pharmacokinetics of ZDV triphosphate. this 10 patient study will be nested into the larger study because of practical limitations of the method, but the same parameters will be investigated. Similarly, a pilot study investigating the pharmacokinetic differences of ZDV phosphorylation in patients on combination ZDV/dideoxycytidine will also be performed in an effort to investigate synergistic efficacy. This study will be nested in site patients enrolled in ACTG 155. Finally, the development of new assays for measurement of intracellular nucleoside analog metabolites is planned. Eventually, modifications of dose to maximize effect might be possible through routine intracellular monitoring of nucleoside analog metabolites.